New hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and processes for their preparation

ABSTRACT

The invention relates to nets hydroxyindoles of the Formula,  
                 
 
     their use as inhibitors of phosphodiesterase 4 and processes for their preparation.

FIELD OF THE INVENTION

[0001] The present invention relates to novel, substitutedhydroxyindoles processes for their preparation, pharmaceuticalpreparations containing these compounds, and a method for the use ofthese compounds which are phosphodiesterase 4 inhibitors, as activecompounds for the treatment of disorders which can be affected byinhibition of phosphodiesterase 4 activity in immunocompetent cells(e.g. macrophages and lymphocytes).

BACKGROUND

[0002] The activation of cell membrane receptors by transmitters leadsto the activation of the second messenger system. Adenylate cyclasesynthesizes active cyclic AMP (cAMP) or cyclic GMP (cGMP) from AMP andGMP. These lead, for example, to relaxation in smooth muscle cells or toinhibition of mediator release or synthesis in inflammatory cells. Thebreakdown of the second messenger cAMP and cGMP is carried out by thephosphodiesterases (PDE). To date, 7 families of PDE enzymes (PDE1-7)are known, which differ by their substrate specificity (cAMP, cGMP orboth) and the dependence on other substrates (e.g. calmodulin). Theseisoenzymes have different functions in the body and are prominent todifferent extents in the individual cell types (Beave J A, Conti M andHeaslip R J, Multiple cyclic nucleotide phosphodiesterases, Mol.Pharmacol. 1994, 46: 399-405; Hall I P, Isoenzyme selectivephosphodiesterase inhibitors; potential clinical uses, Br. J. clin.Pharmacol. 1993, 35: 1-7). As a result of inhibition of the various PDEisoenzyme types, there is an accumulation of cAMP or cGMP in the cells,which can be therapeutically utilized (Torphy T J, Livi G P, ChristensenS B, Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, DrugNews and Perspectives 1993, 6: 203-214).

[0003] In the cells important for allergic inflammation (lymphocytes,mast cells, eosinophilic granulocytes, macrophages), the prevailing PDEisoenzyme is of type 4 (Torphy, J T. and Undem, B. J., Phosphodiesteraseinhibitors: new opportunities for the treatment of asthma, Thorax 1991,46: 512-523). The inhibition of PDE 4 by suitable inhibitors istherefore considered as an important starting point for the therapy of alarge number of allergically induced disorders (Schudt Ch, Dent G, RabeK, Phosphodiesterase Inhibitors, Academic Press London 1996).

[0004] An important property of phosphodiesterase 4 inhibitors is theinhibition of the release of tumour necrosis factor α (TNFα) frominflammatory cells. TNFα is an important pro-inflammatory cytokine,which affects a large number of biological processes. TNFα is released,for example, from activated macrophages, activated T lymphocytes, mastcells, basophils, fibroblasts, endothelial cells and astrocytes in thebrain. It has a self-activating effect on neutrophils, eosinophils,fibroblasts and endothelial cells, as a result of which varioustissue-destroying mediators are released. In monocytes, macrophages andT lymphocytes, TNFα brings about the increased production of furtherpro-inflammatory cytokines such as GM-CSF (granulocyte-macrophagecolony-stimulating factor) or interleukin-8. TNFα plays a central partdue to its inflammation-promoting and catabolic action in a large numberof disorders, such as inflammation of the airways, inflammation of thejoints, endotoxic shock, tissue rejection, AIDS and numerous otherimmunological disorders. Inhibitors of phosphodiesterase 4 are thus alsosuitable for the therapy of disorders of this type which are associatedwith TNFα.

[0005] Chronic obstructive pulmonary diseases (COPD) are widespread inthe population and also have great economic importance. Thus COPDdiseases cause about 10-15% of all illness costs in the developedcountries and about 25% of all cases of death in the USA are to beattributed to this cause (Norman P.: COPD: New developments andtherapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998),however the patients at the time of death are usually over 55 years old(Nolte D.: Chronische Bronchitis—eine Volkskrankheit multifaktoriellerGenese. Atemw.-Lungenkrkh. [Chronic bronchitis—a widespread disease ofmultifactorial origin]. 20 (5), 260-267, 1994). The WHO estimates thatCOPD will be the third most frequent cause of death within the next 20years.

[0006] The syndrome of chronic obstructive lung diseases (COPD)summarizes various syndromes of chronic bronchitis with the symptomscoughing and expectoration and progressive and irreversible impairmentof lung function (exhalation is particularly affected). The course ofthe disease is episodic and often complicated by bacterial infections(Rennard S. I.: COPD: Overview of definitions, Epidemiology, and factorsinfluencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998). Inthe course of the disease, the lung function continuously decreases, thelungs become increasingly emphysematous and the respiratory distress ofthe patients is obvious. This disease clearly adversely affects thequality of life of the patients (dyspnoea, low exercise tolerance) andsignificantly reduces their life expectancy. The main risk factorbesides environmental factors is smoking (Kummer F.: Asthma und COPD.Atemw.-Lungenkrkh. 20 (5), 299-302, 1994; Rennard S. I.: COPD: Overviewof definitions, Epidemiology, and factors influencing its development.Chest, 113 (4) Suppl., 235S-241S, 1998) and therefore men are clearlymore often affected than women. As a result of the change in livinghabits and the increase in the number of smokers, this picture, however,will change in future.

[0007] The current therapy aims only at the alleviation of the symptoms,without causally intervening in the progression of the disease. The useof long-acting Beta2 agonists (e.g. salmeterol) possibly in combinationwith muscarinergic antagonists (e.g. ipratropium) improves the lungfunction by bronchodilatation and is employed routinely (Norman P.:COPD: New developments and therapeutic opportunities, Drugs NewsPerspect. 11 (7), 431-437, 1998). A large part in the COPD episodes isplayed by bacterial infections, which have to be treated withantibiotics (Wilson R.: The role of infection in COPD, Chest, 113 (4)Suppl., 242S-248S, 1998; Grossman R. F.: The value of antibiotics andthe outcomes of antibiotic therapy in exacerbations of COPD. Chest, 113(4) Suppl., 249S-255S, 1998). The therapy of this disease isunsatisfactory as yet, particularly with respect to the continuousdecrease in lung function. New therapeutic approaches which affectinflammatory mediators, proteases or adhesion molecules could be verypromising (Barnes P. J.: Chronic obstructive disease: new opportunitiesfor drug development, TiPS 10 (19), 415-423, 1998).

[0008] Independently of the bacterial infections complicating thedisease, a chronic inflammation which is dominated by neutrophilicgranulocytes is found in the bronchi. The mediators and enzymes releasedby neutrophilic granulocytes, inter alia, have been held responsible forthe structural changes observed in the airways (emphysema). Theinhibition of the activity of the neutrophilic granulocytes is thus arational approach to prevent or to slow down progression of COPD(impairment of lung function parameters). An important stimulus for theactivation of the granulocytes is the pro-inflammatory cytokine TNFα(tumour necrosis factor). Thus it is known that TNFα stimulates theformation of oxygen radicals by neutrophilic granulocytes (Jersmann, H.P. A.; Rathjen, D. A. and Ferrante A.: Enhancement of LPS-inducedneutrophil oxygen radical production by TNFα, Infection and Immunity, 4,1744-1747, 1998). PDE4 inhibitors can very effectively inhibit therelease of TNFα from a large number of cells and thus suppress theactivity of the neutrophilic granulocytes. The non-specific PDEinhibitor pentoxifylline is able to inhibit both the formation of oxygenradicals and the phagocytosability of neutrophilic granulocytes(Wenisch, C.; Zedtwitz-Liebenstein, K.; Parschalk, B. and Graninger W.:Effect of pentoxifylline in vitro on neutrophil reactive oxygenproduction and phagocytic ability assessed by flow cytometry, Clin.Drug. Invest., 13(2):99-104, 1997).

[0009] Various PDE 4 inhibitors are already known. As a matter ofpriority, these are xanthine derivatives, rolipram analogues ornitraquazone derivatives (general survey in: Karlsson J-A, Aldos D,Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin.Ther. Patents 1997, 7: 989-1003). Until now, it was not possible to useany of these compounds clinically. It had to be established that theknown PDE 4 inhibitors also have various side-effects such as nausea andemesis, which it was not possible to suppress adequately until now. Thediscovery of new PDE 4 inhibitors with better therapeutic breadth istherefore necessary.

[0010] Although indoles have been playing an important part for manyyears in the development of new active compounds for variousindications, until now hydroxyindoles were completely unknown asinhibitors of PDE 4.

DESCRIPTION OF THE INVENTION

[0011] The invention relates to substituted hydroxyindoles of theFormula

[0012] and their pharmaceutically acceptable salts, wherein R¹, R⁵ areindependently of each other

[0013] (i) a C₁₋₂ alkyl, straight-chain or branched-chain, optionallymono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆ alkyl,—N(C₁₋₆alkyl)₂, —NHC₆₋₁₄ alkyl, aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆alkyl)(C₁₋₆ aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I, —O—O—C₁₋₁₄aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO₃H, —SO₂R⁶,—OSO₂C₁₋₆ alkyl, —OSO₂C₆₋₁₄, aryl, —(CS)R⁶, —COOH, —(CO)R⁶, mono-, bi-or tricyclic saturated or mono- or polyunsaturated carbocycles havingfrom 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S, where the C₆₋₄ arylgroups and the included carbocyclic and heterocyclic substituents canoptionally be mono- or polysubstituted by R⁴,

[0014] (ii) —C₂₋₁₂ alkenyl, mono- or polyunsaturated, straight-chain orbranched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH₂,—NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆alkyl)(C₆₋₁₄ aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl,—O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO3H,—SO₂R⁶, —OSO₂C₁₋₆ alkyl, —OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH, —(CO)R⁶,mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 3 to 14 ring members, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, which are suitably N, O and S,where the C₆₋₁₄ aryl groups and the included carbocyclic andheterocyclic substituents for their part can optionally be mono- orpolysubstituted by R⁴,

[0015] (iii) mono-, bi- or tricyclic saturated or mono- orpolyunsaturated carbocycles having from 3 to 14 ring members, optionallymono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄ aryl),—NHCOR⁶, —NO₂, —CN, —F. —Cl, —Br, —I, —O—C, alkyl, —O—C₆₋₁₄ aryl,—O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₁₋₆, aryl, —SOR⁶, —SO₃, —SO₂R⁶, —OSO₂C₁₋₆alkyl, —OSO₂C₁₋₆ aryl, —(CS)R⁶, —COOH, —(CO)R⁶, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated carbocycles having from 3 to 14ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S, where the C₆₋₁₄ arylgroups and the included carbocyclic and heterocyclic substituents canoptionally be mono- or polysubstituted by R⁴,

[0016] (iv) mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S, optionally mono- orpolysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂,—NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄ aryl), —NHCOR⁶,—NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl, —O—C₆₋₁₄ aryl, —O(CO)R⁶,—S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO₃H, —SO₂R⁶, —OSO₂C₁₋₆ alkyl,—OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH, —(CO)R⁶, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated carbocycles having from 3 to 14ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S, where the C₆₋₁₄ arylgroups and the included carbocyclic and heterocyclic substituents fortheir part can be optionally mono- or polysubstituted by R⁴, -carbo- orheterocyclic saturated or mono- or polyunsaturated spirocycles havingfrom 3 to 10 ring members, where heterocyclic systems contains from 1 to6 heteroatoms, which are suitably N, O and S, optionally mono- orpolysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂,—NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄ aryl), —NHCOR⁶,—NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl, —O—C₆₋₁₄ aryl, —O(CO)R⁶,—S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO3H, —SO₂R⁶, —OSO₂C₁₋₆ alkyl,—OSO₂C₆₋₁₄ aryl, —(CS)R⁵, —COOH, —(CO)R⁶, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated carbocycles having from 3 to 14ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S, where the C₆₋₁₄ arylgroups and the included carbocyclic and heterocyclic substituents canoptionally be mono- or polysubstituted by R⁴,

[0017] R², R³ are hydrogen or —OH, where at least one of the twosubstituents must be —OH;

[0018] R⁴ is —H, —OH, —SH, —NH₂, —NHC₁₋₆ alkyl, —N(C₆₋₁₄ alkyl)₂,—NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄ aryl), —NHCOR⁶,—NO₂, —CN, —COOH, —(CO)R⁶, —(CS)R⁶, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl,—O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO₂R⁶.

[0019] R⁶ is —H, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl,—N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄ aryl), —O—C₁₋₆ alkyl, —O—C₆₋₁₄aryl, —S—C₆₋₁₄ alkyl, —S—C₆₋₁₄ aryl, —C₁₋₁₂ alkyl, straight-chain orbranched-chain, —C₂ ₂ alkenyl, mono- or polyunsaturated, straight-chainor branched-chain, -mono-, bi- or tricyclic saturated or mono- orpolyunsaturated carbocycles having from 3 to 14 ring members, -mono-,bi- or tricyclic saturated or mono- or polyunsaturated heterocycleshaving from 5 to 15 ring members and from 1 to 6 heteroatoms, which aresuitably N, O and S;

[0020] A is either a bond, or —CH2)_(m)—,—(CH2)_(m)—(CH═CH)_(n)—(CH₂)_(p)—, —(CHOZ)_(m)—, —(C═O)—, —(C═S)—,—(C═N—Z)—, —O—, —S—, —NZ—, where m and p are cardinal numbers from 0 to3 and n is a cardinal number from 0 to 2,

[0021] Z is H, or a C₁₋₁₂ alkyl, straight-chain or branched-chain, C₂₋₁₂alkenyl, mono- or polyunsaturated, straight-chain or branched-chain,mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 3 to 14 ring members, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, which are suitably N, O and S;

[0022] B is either carbon or sulfur, or —(S═O)—;

[0023] D is oxygen, sulfur, CH₂ or N—Z, where D can only be S or CH₂ ifB is carbon;

[0024] E is a bond, or (CH2)_(m)—, —O—, —S—, —(N—Z)—, where m and Z havethe same meanings as above.

[0025] The most suitable compounds of Formula (1) include

[0026]N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

[0027]N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamideNa salt;

[0028]N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;

[0029]N-(pyridin-4-yl)-2-[1-2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

[0030]N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

[0031]N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamideNa salt;

[0032]N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxoacetamide;

[0033]N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;

[0034]N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;

[0035]N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

[0036]N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;

[0037]N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;

[0038]N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide;

[0039]N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide.

[0040] The pharmaceutically acceptable salts are obtained in a customarymanner by neutralization of the bases with inorganic or organic acids orby neutralization of the acids with inorganic or organic bases. Possibleinorganic acids are, for example, hydrochloric acid, sulfuric acid,phosphoric acid or hydrobromic acid, organic acids are, for example,carboxylic, sulfo or sulfonic acids such as acetic acid, tartaric acid,lactic acid, propionic acid, clycolic acid, malonic acid, maleic acid,fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelicacid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid,ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalicacid, amino acids, methanesulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,benzenesulfonic acid, 4-methylbenzenesulfonic acid ornaphthalene-2-sulfonic acid. Possible inorganic bases are, for example,sodium hydroxide solution, potassium hydroxide solution, ammonia, andpossible organic bases are amines, suitably tertiary amines, such astrimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline,isoquinoline, (-picoline, (-picoline, (-picoline, quinaldine orpyrimidine.

[0041] In addition, pharmaceutically acceptable salts of the compound ofFormula (1) can be obtained by converting derivatives which havetertiary amino groups into the corresponding quaternary ammonium saltsin a manner known per se by using quaternizing agents. Possiblequaternizing agents are, for example, alkyl halides such as methyliodide, ethyl bromide and n-propyl chloride, but also arylalkyl halidessuch as benzyl chloride or 2-phenylethyl bromide.

[0042] Furthermore, the invention of the compounds of Formula (1) whichcontain an asymmetric carbon atom relates to the D form, the L form andD,L mixtures and, in the case of a number of asymmetric carbon atoms,the diastereomeric forms. Those compounds of Formula (1) which containasymmetric carbon atoms and as a rule are obtained as racemates can beseparated into the optically active isomers in a manner known per se,for example using an optically active acid. However, it is also possibleto employ an optically active starting substance from the start, acorresponding optically active or diastereomeric compound then beingobtained as the final product.

[0043] The compounds of the present invention have therapeuticallyuseful pharmacological properties as inhibitors of the release of TNFα.These disorders include, for example, arthritides including arthritisand rheumatoid arthritis and other arthritic disorders such asrheumatoid spondylitis and osteoarthritis. Further possibilities oftheir application include the treatment of patients suffering fromsepsis, septic shock, gram-negative sepsis, toxic shock syndrome,respiratory distress syndrome, asthma and other chronic pulmonarydisorders, bone resorption diseases or transplant rejection reactions orother autoimmune disorders, such as lupus erythematosus, multiplesclerosis, glomerulonephritis and uveitis, insulin-dependent diabetesmellitus and chronic demyelinization.

[0044] Moreover, the compounds of the present invention can also beemployed for the therapy of infections such as virus and parasiteinfections, for example, for the therapy of malaria, infection-relatedfever, infection-related myalgia, AIDS and cachexia.

[0045] The compounds according to the invention are inhibitors ofphosphodiesterase 4 (PDE 4). Therefore, the compounds of Formula (1) andtheir salts, and pharmaceutical preparations which contain thesecompounds or their salts, can be used for the treatment of disorders inwhich inhibition of phosphodiesterase 4 is beneficial.

[0046] Thus the compounds according to the invention can be employed asbronchodilators and for asthma prophylaxis. Compounds of Formula (1)also inhibit of the accumulation and activity of eosinophils.Accordingly, the compounds according to the invention can also beemployed in disorders in which eosinophils play a part. These disordersinclude, for example, inflammatory airway disorders such as bronchialasthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis,eczema, allergic angiitis, inflammations mediated by eosinophils such aseosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome(pulmonary infiltration with eosinophilia), urticaria, ulcerativecolitis, Crohn s disease and proliferative skin disorders such aspsoriasis or keratosis.

[0047] According to the present invention the compounds of Formula (1)and their salts can inhibit both the lipopolysaccharide (LPS)-inducedrelease of TNFα in human blood in vitro, and the LPS-induced pulmonaryneutrophilic infiltration in ferrets and domestic pigs in vivo. All thepharmacologically important properties that were found confirm that thecompounds of Formula (1) and their salts as well as pharmaceuticalpreparations which contain these compounds or their salts can be usedtherapeutically for the treatment of chronic obstructive pulmonarydiseases.

[0048] The compounds of the invention also have neuroprotectiveproperties and can be used for the therapy of diseases in whichneuroprotection is beneficial. Such disorders are, for example, seniledementia (Alzheimer's disease), loss of memory, Parkinson's disease,depression, stroke and intermittent claudication.

[0049] Further applications of the compounds of the invention includethe prophylaxis and therapy of prostate diseases, such as, for example,benign prostate hyperplasia, pollakiuria, nycturia; and for thetreatment of atony of the bladder and of colics caused by kidney stones.

[0050] Finally, the compounds according to the invention can also beused for the inhibition of the development of drug dependence onrepeated use of analgesics, such as, for example, morphine, and for thereduction of the development of tolerance on repeated use of theseanalgesics.

[0051] An efficective amount of the compounds according to the inventionor their salts is used for producing medicaments of the presentinvention, along with conventional pharmaceutical auxiliaries, carriersand additives.

[0052] The dose of the active compounds can vary depending on factorssuch as the route of administration, age and weight of the patient,nature and severity of the disorders to be treated and similar factors.Therefore, any reference herein to a pharmacologically effective amountof the compounds of the present invention refers to the aforementionedfactors.

[0053] The daily dose can be given as an individual dose to beadministered once or subdivided into two or more daily doses suitablyfrom about 0.001 mg to about 100 mg each.

[0054] Possible forms of administration include oral, parenteral,intravenous, transdermal, topical, inhalational and intranasalpreparations. For administration, possible customary pharmaceuticaldosage forms include tablets, coated tablets, capsules, dispersiblepowders, granules, aqueous solutions, aqueous or oily suspensions,syrup, juices and drops.

[0055] Solid pharmaceutical forms can contain inert ingredients andcarriers, such as, for example, calcium carbonate, calcium phosphate,sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guargum, magnesium or aluminium stearates, methylcellulose, talc, highlydisperse salicylic acids, silicone oil, high molecular weight fattyacids (such as stearic acid), gelatin, agar-agar or vegetable or animalfats and oils, solid high molecular weight polymers (such aspolyethylene glycol); preparations suitable for oral administration can,if desired, contain additional flavorings and/or sweeteners.

[0056] Liquid pharmaceutical forms can be sterilized and/or optionallycontain auxiliaries such as preservatives, stabilizers, wetting agents,penetrating agents, emulsifiers, spreading agents, solubilizers, salts,sugars or sugar alcohols for regulation of the osmotic pressure or forbuffering, and/or viscosity regulators.

[0057] Additives of this type include, for example, tartrate and citratebuffers, ethanol, complexing agents (such as ethylenediaminetetraaceticacid and its nontoxic salts). For regulation of the viscosity, possiblehigh molecular weight polymers are those such as, for example, liquidpolyethylene oxide, microcrystalline celluloses,carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin.Solid carriers include, for example, starch, lactose, mannitol,methylcellulose, talc, highly disperse salicylic acids, high molecularweight fatty acids (such as stearic acid), gelatin, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats, solid highmolecular weight polymers such as polyethylene glycol.

[0058] Oily suspensions for parenteral or topical application caninclude vegetable synthetic or semi-synthetic oils such as, for example,liquid C₈₋₂₂ fatty acid esters, for example palmitic, lauric,tridecylic, margaric, stearic, arachidic, myristic, behenic,pentadecanoic, linoleic, elaidic, brassidic, erucic or oleic acid, whichare esterified with mono- to C₁₋₆ trihydric alcohols, such as, forexample, methanol, ethanol, propanol, butanol, pentanol or theirisomers, glycol or glycerol. Fatty acid esters of this type are, forexample, commercially available Miglyols, isopropyl myristate, isopropylpalmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acidesters of saturated fatty alcohols, polyoxyethylene glycerol trioleates,ethyl oleate, waxy fatty acid esters such as artificial duck preen glandfat, isopropyl cocoate, oleyl oleate, decyl oleate, ethyl lactate,dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters andothers. Also suitable are silicone oils of differing viscosities orfatty alcohols such as isotridecyl alcohol, 2-octyldodecanol,cetylstearyl alcohol or oleyl alcohol, fatty acids such as, for example,oleic acid. Furthermore, vegetable oils such as castor oil, almond oil,olive oil, sesame oil, cottonseed oil, groundnut oil or soya bean oilcan be used.

[0059] Possible solvents, gel-forming agents and solubilizers are wateror water-miscible solvents. Those suitable are, for example, alcoholssuch as, for example, ethanol or isopropyl alcohol, benzyl alcohol,2-octyldodecanol, polyethylene glycols, phthalates, adipates, propyleneglycol, glycerol, di- or tripropylene glycol, waxes, methylcellosolve,cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide,dimethylformamide, tetrahydrofuran, cyclohexanone etc.

[0060] Film-forming agents which can be used are cellulose ethers whichcan dissolve or swell both in water and in organic solvents, such as,for example, hydroxypropylmethylcellulose, methylcellulose,ethylcellulose or soluble starches.

[0061] Mixed forms between gel- and film-forming agents are alsopossible. Those used here are especially ionic macromolecules, such as,for example, sodium carboxymethylcellulose, polyacrylic acid,polymethacrylic acid and its salts, sodium amylopectin semiglycolate,alginic acid or propylene glycol alginate as the sodium salt, gumarabic, xanthan gum, guar gum or carrageenan.

[0062] Further formulation auxiliaries which can be employed includeglycerol, paraffin of differing viscosities, triethanolamine, collagen,allantoin, novantisolic acid.

[0063] The use of surfactants, emulsifiers or wetting agents can also benecessary for formulation, such as, for example, of Na lauryl sulfate,fatty alcohol ether sulfates, di-Na N-lauryl-(-iminodipropionate,polyethoxylated castor oil or sorbitan monooleate, sorbitanmonostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin,glycerol monostearate, polyoxyethylene stearate, alkylphenyl polyglycolethers, cetyltrimethylammonium chloride or mono-/dialkyl polyglycolether orthophosphoric acid monoethanolamine salts.

[0064] Stabilizers such as montmorillonites or colloidal salicylic acidsfor the stabilization of emulsions or for the prevention of thebreakdown of the active substances, such as antioxidants, for exampletocopherols or butylhydroxyanisole, or preservatives, such asp-hydroxybenzoic acid esters, can likewise optionally be required forthe preparation of the desired formulations.

[0065] Preparations for parenteral administration can be present inseparate dose unit forms such as, for example, ampoules or vials.Suitably, solutions of the active compound are used, most suitablyaqueous solutions and especially isotonic solutions, and alsosuspensions. These injection forms can be made available as finishedpreparations or prepared only directly before administration by mixingthe active compound, for example the lyophilizate, if appropriate withfurther solid carriers, with the desired solvent or suspending agent.

[0066] Intranasal preparations can be present as aqueous or oilysolutions or as aqueous or oily suspensions. They can also be present aslyophilizates, which are prepared before administration using thesuitable solvent or suspending agent.

[0067] The production, dispensation and sealing of the preparations iscarried out under the conventional antimicrobial and aseptic conditions.

[0068] The invention furthermore relates to processes for thepreparation of the compounds according to the invention.

[0069] According to the invention, the compounds of Formula (1) areprepared by converting compounds of Formula (1), wherein R² or R³ or R²and R³ are —O—R⁷, into the compounds of the invention by removal of R⁷,wherein R⁷ is a substituent suitable as a leaving group, such as, forexample, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl,alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substitutedaminocarbonyl, silyl or sulfonyl groups, and complexing agents, such as,for example, compounds of boric acid, phosphoric acid and covalently orcoordinatively bonded metals, such as zinc, aluminium or copper.

[0070] Particularly suitable reactions for the removal of R⁷ arehydrolyses using suitable bases, such as, for example, sodium hydroxidesolution, potassium hydroxide solution or sodium carbonate or potassiumcarbonate.

[0071] These hydrolyses are suitably used when R⁷ is an acyl,alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substitutedaminocarbonyl, silyl or sulfonyl residue, and a complexing agent, suchas, for example, compounds of boric acid, phosphoric acid andcoordinatively bonded metals, such as zinc, aluminium or copper.Particularly suitable reactions for preparing the compounds of theinvention for the removal of R⁷ from the compounds in which R⁷ is analkyl, cycloalkyl, arylalkyl, aryl or heteroaryl residue, are ethercleavages, for example by means of hydrobromic acid, hydrochloric acid,hydriodic acid, and using activating Lewis acids, such as, for example,AlCl3, BF3, BBr₃ or LiCl, in each case optionally in the presence ofadditional activators, such as, for example, ethane-1,2-dithiol orbenzyl mercaptan, and ether cleavages by means of hydrogen, at elevatedpressure or at normal pressure, in the presence of a suitable catalyst,such as, for example, a palladium or iridium catalyst.

[0072] According to the invention, the compounds of Formula (1) can alsobe prepared by converting the substructure:

[0073] of compounds of Formula (1) by a reaction known per se into othercompounds of Formula (1). Particularly suitable conversion reactionswith compounds of Formula (1) are, for example, when A is —(C═O),reductions to result in A being —(CH—OH)— or A being —CH₂—, by reducingagents known per se, such as, for example, sodium borohydride, or byhydrogenations, which can optionally also be carried outstereoselectively.

[0074] Further suitable conversion reactions are the conversion ofcompounds in which D and B are oxygen into substances in which only D isoxygen, but E is —(N—Z)—, where Z has the definition given above.

[0075] Exemplary processes show below the preparation of compounds ofFormula (1) according to the invention from starting substances of thetype described, in which R⁷ is an alkyl, cycloalkyl, arylalkyl, aryl orheteroaryl residue.

EXAMPLE 1N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide

[0076] 1.4 g ofN-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2-oxoacetamide(3 mmol) is dissolved in 100 ml of dichloromethane. The solution isheated to reflux and treated with a solution of 14 mmol of BBr₃ in 15 mlof dichloromethane with stirring. The reaction mixture is refluxed for 3hours. After cooling, the solution is intensively stirred for 3 hours at20° C. with 200 ml of an aqueous sodium hydrogencarbonate solution. Theproduct crystallizes out, it is isolated, dried at 60° C. andrecrystallized from 80 ml of ethanol.

[0077] Yield: 1.1 g (80% of theory)

[0078] melting point: 213-214° C.

EXAMPLE 2N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide

[0079] 5 g (38 mmol) anhydrous aluminium chloride is introduced into 50ml ethane-1,2,-dithiol. A solution of 4.7 g ofN-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2-oxoacetamide(10 mmol) in 50 ml of dichloromethane is added at 0° C. The mixture isstirred at 0° C. for 4 hours. 50 ml of 10% hydrochloric acid is addeddropwise at from 0 to 10° C. with stirring. The crystallizing product isisolated, washed with water and dried at 20° C. A pure product isobtained by recrystallization from ethanol (180 ml).

[0080] Yield: 3.1 g (67% of theory)

[0081] Melting point: 212-214° C.

[0082] Exemplary preparative process as follows for compounds of Formula(1) from starting substances of the type described, in which R⁷ is anacyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substitutedaminocarbonyl, silyl or sulfonyl residue:

EXAMPLE 3N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamideNa Salt

[0083] 5 g ofN-(3,5-dichloropyridin-4-yl)-2-[5-acetoxy-1-(4-fluorobenzyl)-indol-3-yl]-2-oxoacetamide(10 mmol) are stirred at 40° C.-50° C. for 1 hour in 50 ml dilute sodiumhydroxide solution. The solution is neutralized with 10% hydrochloricacid while cooling with ice, and is concentrated to dryness. The residueis dissolved in 80 ml acetone and insoluble constituents are removed.The clear solution is treated with a solution of 0.4 g NaOH in 3 ml ofwater and stirred at 20° C. for 2 hours. The crystallized product isisolated, washed with acetone and dried at 60° C.

[0084] Yield: 2.44 g (51% of theory)

[0085] Melting point: 265° C.

[0086] An exemplary preparation process follows for compounds of Formula(1) from other compounds of Formula (1).

EXAMPLE 4N-(3,5-Dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide

[0087] 1 g ofN-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide(1; 2 mmol) are suspended in 75 ml methanol. After addition of asolution of 0.2 g of sodium borohydride in 3 ml dilute sodium hydroxidesolution, the reaction mixture is stirred at 20° C. for 6 hours. Afterthe solvent has been removed by distillation, the residue isrecrystallized from 40 ml ethanol.

[0088] Yield: 0.5 g (50% of theory)

[0089] Melting point: 205-207° C.

[0090] Numerous further compounds of Formula (1) can be prepared, asshown in the Examples and also in the further examples, all summarizedin the next table. Melting point Ex. R¹ R² R³ R⁴ R⁵ A B D E [° C.] 14-Fluorobenzyl —OH —H —H 3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)— 2152 4-Fluorobenzyl —O⁻ —H —H 3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)—265 Na⁺ 3 4-Fluorobenzyl —OH —H —H 3,5-Dichloro-4-pyridyl —(CHOH)— C O—(N—H)— 205-207 4 2,6-Difluorobenzyl —OH —H —H 4-Pyridyl —(C═O)— C O—(N—H)— 327-329 5 2,6-Difluorobenzyl —OH —H —H 3,5-Dichloro-4-pyridyl—(C═O)— C O —(N—H)— 266-268 6 3-Nitrobenzyl —O⁻ —H —H3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)— 235-238 Na⁺ dec. 7 n-Propyl—OH —H —H 3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)— 280-282 8 Isopropyl—OH —H —H 3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)— 245-247 9Cyclopentylmethyl —OH —H —H 3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)—246-248 10 4-Fluorobenzyl —OH —H —H 2,6-Dichlorophenyl —(C═O)— C O—(N—H)— 216-218 11 4-Fluorobenzyl —OH —H —H 2,6-Dichloro-4- —(C═O)— C O—(N—H)— 199-201 trifluoromethylphenyl 12 4-Fluorobenzyl —OH —H —H2,6-Dichloro-4- —(C═O)— C O —(N—H)— 176-178 trifluoromethoxyphenyl 134-Fluorobenzyl —H —OH —H 3,5-Dichloro-4-pyridyl —(C═O)— C O —(N—H)—212-213 14 4-Methoxybenzyl —OH —H —H 3,5-Dichloro-4-pyridyl — C O—(N—H)— 239-241

[0091] The compounds according to the invention are strong inhibitors ofphosphodiesterase 4 and TNFα, release. Their therapeutic potential isconfirmed in vivo, for example, by the inhibition of the asthmaticlate-phase reaction (eosinophilia) in guinea-pigs and by the influencingof the allergen-induced vascular permeability in actively-sensitizedbrown Norway rats.

[0092] The PDE 4 inhibiting activity is determined in enzymepreparations of human polymorphonuclear lymphocytes (PMNLs), the PDE 2,3 and 5 activity with PDE from human platelets. Human blood wasanticoagulated with citrate. The thrombocyte-rich plasma in thesupernatant is separated from the erythrocytes and leucocytes bycentrifugation at 700× g for 20 minutes at RT. The platelets are lysedby ultrasound and employed in the PDE 3 and PDE 5 assay. For thedetermination of the PDE 2 activity, the cytosolic platelet fraction ispurified on an anion exchange column by means of NaCl gradients and thePDE 2 peak is recovered for the assay. The PMNLs for the PDE 4determination are isolated by a following dextran sedimentation andsubsequent gradient centrifugation using Ficoll-Paque. After a secondwashing of the cells, the erythrocytes still contained are lysed in thecourse of 6 minutes at 4° C. by the addition of 10 ml of hypotonicbuffer (155 mM NH₄Cl, 10 mM NaHCO₃, 0.1 mM EDTA, pH 7.4). The stillintact PMNLs are washed with PBS a further two times and lysed by meansof ultrasound. The supernatant of a one-hour centrifugation at 4° C. at48,000× g contains the cytosolic fraction of the PDE 4 and is employedfor the PDE 4 measurements.

[0093] The phosphodiesterase activity is determined with somemodifications according to the method described by Thompson et al.(Thompson, W. J.; Appleman, M. M., Assay of cyclic nucleotidephosphodiesterase and resolution of multiple molecular forms of theenzyme, Adv. Cycl. Nucl. Res. 1979, 10, of multiple molecular forms ofthe enzyme, Adv. Cycl. Nucl. Res. 1979, 10, 69-92).

[0094] The reaction mixtures contain 50 mM tris HCl (pH 7.4), 5 mMMgCl₂, the inhibitors in variable concentrations, the correspondingenzyme preparation and also the further components necessary for thedetection of the individual isoenzymes (see below). The reaction isstarted by the addition of the substrate 0.5 μM [³H]-cAMP or [³H]-cGMP(about 6000 CPM/test). The final volume is 100 ml. Test substances areprepared as stock solutions in DMSO. The DMSO concentration in thereaction mixture is 1% v/v. At this DMSO concentration, the PDE activityis not affected. After the start of the reaction by means of substrateaddition, the samples are incubated at 37° C. for 30 minutes. Thereaction is stopped by heating the test tubes for 2 minutes at 110° C.The samples remain in the ice for a further 10 minutes. After theaddition of 30 μl of 5-nucleotidase (1 mg/ml, of a snake venomsuspension from Crotalus adamanteus) incubation is carried out for 10minutes at 37° C. The samples are stopped on ice, 400 μl each of amixture of Dowex-water-ethanol (1+1+1) are added, and the samples arewell mixed and again incubated on ice for 15 minutes. The reactionvessels are centrifuged at 3000× g for 20 minutes. 200 μl aliquots ofthe supernatant are transferred directly to scintillation vessels. Afterthe addition of 3 ml of scintillator, the samples are measured in a betacounter.

[0095] [³H]-cAMP is used as a substrate for the determination of the PDE4, 3 and 2 activity, [³H]-cGMP for the determination of the PDE 5activity. The non-specific enzyme activities in each case are determinedin the presence of 100 [μM rolipram in the case of PDE 4 and in thepresence of 100 μM IBMX in the determination of PDE 3 and 5 andsubtracted from the test values. The incubation batches of the PDE 3assay contain 10 μM rolipram in order to inhibit possible contaminationby the PDE 4. The PDE 2 is tested using an SPA assay from Amersham. Theassay is carried out in the presence of the activator of PDE 2 (5 μMcGMP).

[0096] IC₅₀ values in the range from 10⁻⁹ to 10⁻⁵ M were calculated forthe compounds according to the invention in relation to the inhibitionof phosphodiesterase 4. The selectivity to the PDE types 2, 3 and 5 isfactor 100 to 10,000.

[0097] For the determination of the inhibition of TNFα release fromcells of nasal polyps, the experimental arrangement essentiallycorresponds to the method described by Campbell, A. M. and Bousquet J(Anti-allergic activity of H₁-blockers, Int. Arch. Allergy Immunol.,1993, 101, 308-310). The starting material is nasal polyps (obtainedfrom operation) of patients who have been subjected to surgicaltreatment.

[0098] The tissue is washed with RPMI 1640 and then broken down at 37°C. for 2 hours using protease (2.0 mg/ml), collagenase (1.5 mg/ml),hyaluronidase (0.75 mg/ml) and DNAse (0.05 mg/ml) (1 g of tissue to 4 mlof RPMI 1640 with enzymes). The cells obtained, a mixture of epithelialcells, monocytes, macrophages, lymphocytes, fibroblasts andgranulocytes, are filtered and washed by repeated centrifugation innutrient solution, passively sensitized by addition of human IgE and thecell suspension is adjusted to a concentration of 2 million cells/ml inRPMI 1640 (supplemented with antibiotics, 10% foetal calf serum, 2 mMglutamine and 25 mM Hepes). This suspension is distributed in 6-wellcell culture plates (1 me/well). The cells are preincubated for 30 minwith the test substances in various final concentrations and thenstimulated to TNFα release by addition of anti-IgE (7.2 μg/ml). Themaximum release into the nutrient medium takes place after about 18hours. In this period, the cells are incubated at 37° C. and 5% CO₂. Thesupernatant nutrient medium is recovered by centrifugation (5 min, 4000rpm) and stored at −70° C. until cytokine determination. Thedetermination of TNFα in the supernatant is carried out using so-calledsandwich ELISAs (basic material Pharmingen), in which concentrations ofthe cytokine in the range from 30-1000 pg/ml can be detected.

[0099] Cells not stimulated with anti-IgE barely produce TNFα,stimulated cells, however, secrete large amounts of TNFα, which can bedecreased in a dose-dependant manner, for example, by PDE 4 inhibitors.The IC₅₀ (concentration at 50% inhibition) is calculated from thepercentage inhibition (TNFα release of the cells stimulated withanti-IgE=100%) of the tested substances at various concentrations.

[0100] For the compounds according to the present invention, lC₅₀ valuesin the range of 10⁻⁷ to 10⁻⁵ M were determined.

[0101] The inhibition of the pulmonary eosinophil infiltration by thesubstances is investigated in an in vivo test of the inhibition of thelate-phase eosinophilia 24 hours after inhalational ovalbumin challengeof actively sensitized guinea-pigs on male Dunkin-Hartley guinea-pigs(200-250 g) actively sensitized against ovalbumin (OVA). Thesensitization is carried out by means of two intraperitoneal injectionsof a suspension of 20 μg of OVA together with 20 mg of aluminiumhydroxide as an adjuvant in 0.5 ml of physiological saline solution peranimal on two successive days. 14 days after the second injection, theanimals are pretreated with mepyramine maleate (10 mg/kg i.p.) in orderto protect them from anaphylactic death. 30 minutes later, the animalsare exposed for 30 sec in a plastic box to an OVA aerosol (0.5 mg/ml)which is generated by a nebulizer driven with compressed air (19.6 kPa)(allergen challenge). Control animals are nebulized with physiologicalsaline solution. 24 hours after the challenge, the animals areanaesthetized with an overdose of ethylurethane (1.5 g/kg of body weighti.p.) and a bronchoalveolar lavage (BAL) is carried out using 2×5 ml ofphysiological saline solution. The BAL fluid is collected, centrifugedat 300 rpm for 10 min and the cell pellet is then resuspended in 1 ml ofphysiological saline solution. The eosinophils in the BAL are countedusing an automatic cell differentiation apparatus (Bayer DiagnosticsTechnicon H1). 2 control groups (nebulization with physiological salinesolution and nebulization with OVA solution) are included in each test.

[0102] The percentage inhibition of eosinophilia of the test grouptreated with substance is calculated according to the formula:${\% \quad {inhibition}} = {100 - \frac{100 \times \left( {B - C} \right)}{\left( {A - C} \right)}}$

[0103] wherein

[0104] A is eosinophils in the control group with OVA challenge andvehicle

[0105] B is eosinophils in the group with OVA challenge treated withsubstance

[0106] C is eosinophils in the control group with 0.9% strength NaClchallenge and vehicle

[0107] The test substances are administered intraperitoneally or orallyas a suspension in 10% polyethylene glycol 300 and 0.5% strength5-hydroxy-ethylcellulose 2 hours before the allergen challenge. Thecontrol groups are treated with the vehicle according to the form ofadministration of the test substance.

[0108] The compounds according to the invention were found to inhibitlate-phase eosinophilia by 30% to 80% after intraperitonealadministration of 10 mg/kg and by 40% to 70% after oral administrationof 30 mg/kg. The compounds according to the invention are thusparticularly suitable for the production of drugs for the treatment ofdisorders which are connected with the action of eosinophils.

[0109] The effect of allergen-induced vascular permeability wasdetermined on actively sensitized male brown Norway rats. Male brownNorway rats weighing 280-300 g are actively sensitized on 2 successivedays by intraperitoneal injection of a suspension of 1 mg of ovalbumintogether with 100 mg of aluminium hydroxide in 1 ml/animal. Three weeksafter sensitization, the rats are anaesthetized with sodium thiopentaland fixed in the supine position. A polyethylene catheter was advancedinto the trachea in a backward direction as far as the internal openingof the choanas for perfusion of the nasal cavity, so that it waspossible for the solution to trickle out through the nasal cavities. Ashort tracheal catheter was tied into the trachea in an orthogrademanner to make respiration possible. Phosphate-buffered saline solution(PBS) was continuously pumped for perfusion through the nasal cavity(0.5 ml/min) using a roller pump and collected by means of a fractioncollector. Evans Blue was used as a plasma marker and injectedintravenously (1 ml/animal each of a 1% strength solution in PBS)through a catheter in the jugular vein.

[0110] Substance administration was carried out topically. Duringadministration, the test substance was added to the perfusion medium(PBS). The nasal mucous membrane was perfused for 30 min with PDE 4inhibitor-containing solution. Evans Blue was then injected immediatelybefore the start of the perfusion with ovalbumin-containing solution(challenge). After the start of the ovalbumin challenge (10 mg/ml ofovalbumin dissolved in PBS) 15 min fractions were collected every 15 minin the fraction collector over a period of 60 min. The Evans Blueconcentration in the perfusates was measured with a Digiscan photometerat a wavelength of 620 nm. The blank values were automaticallysubtracted in the course of this. The course of action over 60 min wascalculated using an AUC program. The substance action of the preparationgroup was calculated against vehicle controls in %.

[0111] IC₅₀ values in the range from 10⁻⁸ to 10⁻⁵ M were determined forthe compounds of the present invention.

[0112] The utility of the compounds according to the invention ofFormula (I) for the therapy of chronic obstructive pulmonary diseases isconfirmed by the inhibition of LPS-induced TNFα release in human bloodand by the inhibition of LPS-induced pulmonary neutrophil infiltrationin ferrets and domestic pigs, all good animal models.

[0113] The stimulation of isolated leucocytes to cytokine release cantake place in various ways. Lipopolysaccharides (LPSs) are a stimulussuitable for the investigation of TNFα release. LPS is a constituent ofthe bacterial cell walls and is released by killing the bacteria(antibiotics or immune system). LPS particularly stimulates the activityof the phagocytizing leucocytes (tissue macrophages, granulocytes,monocytes) and causes the infiltration of leucocytes from the bloodstream into the affected tissue. A cytokine important for thesemechanisms is TNFα, which is secreted in large amounts by the affectedcells (the monocytes and macrophages are the main source) and initiatesand maintains inflammation alongside other mediators.

[0114] For the investigation of the effect on LPS-induced TNFα release,human blood was obtained from various donors (inhibition of coagulationby means of citrate) and diluted 1:5 with RPMI 1640 cell culture medium.The test substances were added to the samples in various concentrationsbefore the LPS challenge. The stimulation of the leucocytes was carriedout 30 min later using lipopolysaccharides (LPS) from Salmonella abortusequi in a final concentration of 10 μg/ml. After incubation of the testbatches for 24 hours at 37° C. and under 5% CO₂ in an incubator, thediluted blood was centrifuged and the TNFα concentration in thecell-free supernatant was measured by means of ELISA.

[0115] IC₅₀ values in the range from 10⁻⁷ to 10⁻⁵ M were determined forthe compounds according to the invention. An IC₅₀ value of 0.8 μmol/l,for example, was determined for the compound as in Example 1. Incomparison with this, an IC₅₀ value of 7.0 μmol/l was determined withthe reference standard SB 207499.

[0116] The inhibition of lipopolysaccharide (LSP)-induced pulmonaryneutrophil infiltration by the substance is investigated in an in vivotest on male ferrets (0.6-2 kg). The experimental animals areanaesthetized with pentobarbital sodium (40 mg/kg of body weight i.p.),placed individually into a closed nebulization box of 5 l capacity andexposed to an ultrasonically nebulized aerosol of 0.01% strength LPS(lipopolysaccharide) solution (additionally 0.1% hydroxylamine in PBS)for 10 minutes. The aerosol is generated by a nebulizer driven withcompressed air (0.2 Mpa). Control animals are treated with an aerosol ofphysiological saline solution. The animals are observed during theentire process and removed from the nebulization box after admission offresh air. On inhalation, nebulized LPS immediately induces inflammationof the airways, which is characterized by a massive infiltration ofneutrophilic granulocytes into the lungs of the experimental animals.The neutrophilia achieves its maximum 4 to 6 hours after LPS exposure.In order to be able to measure the number of infiltrated neutrophilicgranulocytes, the animals are anaesthetized with an overdose ofethylurethane (1.5 g/kg of body weight i.p.) 6 hours after LPSprovocation and a bronchoalveolar lavage (BAL) is carried out using 2×10ml of physiological saline solution. The number of cells in the pooledoriginal BAL fluid (100 μl) are determined using the automaticcell-counting apparatus sold by Bayer Diagnostic under the tradedesignation Technicon H1E and the different leucocytes per μl aredifferentiated. In each test, 2 control groups (nebulization withphysiological saline solution or with LPS solution) are included.Substances having anti-inflammatory activity, particularly those whichaffect TNFα release or the function of the neutrophilic granulocytes,inhibit the infiltration of leucocytes. The inhibition of infiltrationis determined by the comparison of the number of infiltrated neutrophilsin untreated experimental animals (with and without LPS provocation).

[0117] ID₅₀ values in the range from 1 to 20 mg/kg i.p. were determinedfor the compounds according to the invention. The compound of Example 1was administered in doses of 1, 3 and 10 mg/kg i.p. 2 hours before LPSprovocation to up to 3 experimental animals per dose. The neutrophiliain the BAL was inhibited in a dose-dependent manner (18%, 64% and 78%).The ID₅₀ is 2.4 mg/kg i.p. The administration of the selected PDE 4inhibitor RPR-73401 (reference substance) caused an inhibition ofneutrophilia of 49% in the dose 1 mg/kg i.p.

[0118] For intrapulmonary administration, the trachea of the animals isopened under anaesthesia with 40 mg/kg i.p. of pentobarbital sodium, 3%strength, 1.3 ml/kg, a 7 cm-long PVC catheter is tied in and the testsubstances are administered intrapulmonarily in powder form (mixed withlactose to 20 mg/kg) by means of a syringe 2 hours before LPSprovocation. The intrapulmonary administration of Example 1 in doses of1, 3 and 10 mg/kg inhibits LPS-induced neutrophilia in a dose-dependentmanner (43%, 65% and 100%). The ID₅, is 1.65 mg/kg i.palm.

[0119] Pulmonary neutrophilia can be induced with LPS in domestic pigsin a manner similar to that in the ferret. The animals are anaesthetizedwith pentobarbital 10 mg/kg i.v., and intubated. Using a bronchoscope, apartial bronchoalveolar lavage is carried out in order to determine theproportion of neutrophilic granulocytes under physiological conditions.The test substance is then administered and the animals inhale anultrasonically nebulized aerosol of 0.03% strength LPS(lipopolysaccharide) solution (additionally 0.1% hydroxylamine in PBS)through the tracheal tube for 20 min. The inhaled LPS induces a reactiveinflammation of the airways and neutrophilic granulocytes infiltrate ona huge scale. The neutrophilia achieves its maximum 4 to 6 hours afterLPS exposure. After 6 hours, the bronchoalveolar lavage is repeated andthe increase in the neutrophil count is determined arithmetically.

[0120] Among animal species, the pig is particularly suitable for theseinvestigations, since is has large anatomical and physiologicalsimilarities to man. For the compounds according to the invention,inhibitions of LPS-induced neutrophilia of 20% to 65% were determined onintrapulmonary administration of 10 mg/animal.

[0121] The intrapulmonary administration of the compound of Example 1 inthe dose 10 mg/animal (about 0.75 mg/kg) inhibited LPS-induced pulmonaryneutrophilia by 51%.

We claim:
 1. A compound of the Formula

and their pharmaceutically acceptable salts, wherein R¹, R⁵ areindependently of each other (i) a C₁₋₂ alkyl, straight-chain orbranched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH₂,—NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆alkyl)(C₆₋₁₄ aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl,—O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO₃H,—SO₂R⁶, —OSO₂C₆₋₁₄ alkyl, —OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH, —(CO)R⁶,mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 3 to 14 ring members, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, which are suitably N, O and S,where the C₆₋₄ aryl groups and the included carbocyclic and heterocyclicsubstituents can optionally be mono- or polysubstituted by R⁴,(ii)-C₂₋₁₂ alkenyl, mono- or polyunsaturated, straight-chain orbranched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH₂,—NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆alkyl)(C₆₋₁₄ aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl,—O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO3H,—SO₂R⁶, —OSO₂C₁₋₆ alkyl, —OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH, —(CO)R⁶,mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 3 to 14 ring members, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, which are suitably N, O and S,where the C₆₋₁₄ aryl groups and the included carbocyclic andheterocyclic substituents for their part can optionally be mono- orpolysubstituted by R⁴, (iii) mono-, bi- or tricyclic saturated or mono-or polyunsaturated carbocycles having from 3 to 14 ring members,optionally mono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆ alkyl,—N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl, —O—C₆₋₁₄aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO₃H, —SO₂R⁶,—OSO₂C₁₋₆ alkyl, —OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH, —(CO)R⁶, mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles having from3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S, where the C₆₋₁₄ arylgroups and the included carbocyclic and heterocyclic substituents canoptionally be mono- or polysubstituted by R⁴, (iv) mono-, bi- ortricyclic saturated or mono- or polyunsaturated heterocycles having from5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N,O and S, optionally mono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆alkyl)(C₆₋₁₄ aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆ alkyl,—O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —SOR⁶, —SO₃H,—SO₂R⁶, —OSO₂C₁₋₆ alkyl, —OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH, —(CO)R⁶,mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 3 to 14 ring members, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, which are suitably N, O and S,where the C₆₋₁₄ aryl groups and the included carbocyclic andheterocyclic substituents for their part can be optionally mono- orpolysubstituted by R⁴, -carbo- or heterocyclic saturated or mono- orpolyunsaturated spirocycles having from 3 to 10 ring members, whereheterocyclic systems contains from 1 to 6 heteroatoms, which aresuitably N, O and S, optionally mono- or polysubstituted by —OH, —SH,—NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂,—N(C₁₋₆ alkyl)(C₆₋₁₄ aryl), —NHCOR⁶, —NO₂, —CN, —F, —Cl, —Br, —I,—O—C₁₋₆ alkyl, —O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl,—SOR⁶, —SO3H, —SO₂R⁶, —OSO₂C₁₋₆ alkyl, —OSO₂C₆₋₁₄ aryl, —(CS)R⁶, —COOH,—(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 3 to 14 ring members, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, which are suitably N, O and S,where the C₆₋₁₄ aryl groups and the included carbocyclic andheterocyclic substituents can optionally be mono- or polysubstituted byR⁴, R², R³ are hydrogen or —OH, where at least one of the twosubstituents must be —OH; R⁴ is —H, —OH, —SH, —NH₂, —NHC₁₋₆ alkyl,—N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄ aryl, —N(C₆₋₁₄ aryl)₂, —N(C₆₋₁₄ alkyl)(C₆₋₁₄aryl), —NHCOR⁶, —NO₂, —CN, —COOH, —(CO)R⁶, —(CS)R⁶, —F, —Cl, —Br, —I,—O—C₆₋₁₄ alkyl, —O—C₆₋₁₄ aryl, —O(CO)R⁶, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl,—SOR⁶, —SO₂R⁶. R⁶ is —H, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —NHC₆₋₁₄aryl, —N(C₆₋₁₄ aryl)₂, —N(C₁₋₆ alkyl)(C₆₋₁₄ aryl), —O—C₁₋₆ alkyl,—O—C₆₋₁₄ aryl, —S—C₁₋₆ alkyl, —S—C₆₋₁₄ aryl, —C₁₋₁₂ alkyl,straight-chain or branched-chain, —C₂₋₁₂ alkenyl, mono- orpolyunsaturated, straight-chain or branched-chain, -mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles having from3 to 14 ring members, -mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S; A is either a bond, or—CH2)_(m)—, —(CH2)_(m)—(CH═CH)_(n)—(CH₂)_(p)—, —(CHOZ)_(m)—, —(C═O)—,—(C═S)—, —(C═N—Z)—, —O—, —S—, —NZ—, where m and p are cardinal numbersfrom 0 to 3 and n is a cardinal number from 0 to 2, Z is H, or a C₁₋₁₂alkyl, straight-chain or branched-chain, C₂₋₁₂ alkenyl, mono- orpolyunsaturated, straight-chain or branched-chain, mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles having from3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, which are suitably N, O and S; B is either carbon orsulfur, or —(S═O)—; D is oxygen, sulfur, CH₂ or N—Z, where D can only beS or CH₂ if B is carbon; E is a bond, or (CH2)_(m)—, —O—, —S—, —(N—Z)—,where m and Z have the same meanings as above.
 2. The compound of claim1, wherein the compound is a pharmaceutically acceptable salt of anorganic or inorganic acid, or of an organic or inorganic base, or aquaternary ammonium salt from the quaternization of a tertiary amine. 3.The compound of claim 1, having an asymetric carbon atom by being the Lor the D form, or a D,L mixture, and when in a diastereoisomeric form.4. A compound of claim 1, being one of the following compounds:N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamideNa salt;N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;N-(pyridin-4-yl)-2-[1-2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxyacetamide;N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamideNa salt;N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxyacetamide;N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide;N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide.5. A process for preparing compounds of claim 1, which comprisesconverting a compound of claim 1 wherein R₁ or R³, or R² and R³ is —O—R⁷in which R₇ is a leaving group.
 6. The process of claim 5, wherein saidleaving group is alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl,alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substitutedaminocarbonyl, silyl or sulfonyl residue or a complexing agent.
 7. Theprocess of claim 6, wherein said complexing agent is a compound of boricacid or phosphoric acid, or a compound containing a covalently bondedmetal.
 8. The process of claim 7, wherein said metal is zinc, aluminum,or copper.
 9. A process for preparing compounds of claim 1, whichcomprises converting the substructure

into another compound of claim
 1. 10. A process for inhibiting TNFα byadministering to a patient in need therefor an effective amount of thecompound of claim
 1. 11. A process for inhibiting TNFα by administeringto a patient in need therefor an effective amount of the compound ofclaim
 4. 12. A process for inhibiting phosphodiesterase 4 byadministering to a patient in need therefor an effective amount of thecompound of claim
 1. 13. A process for inhibiting phosphodiesterase 4 byadministering to a patient in need therefor an effective amount of thecompound of claim
 4. 14. A process for treating an eosinophil-relatedcondition by administering to a patient in need therefor an effectiveamount of the compound of claim
 1. 15. A process for treating aneosinophil-related condition by administering to a patient in needtherefor an effective amount of the compound of claim
 4. 16. A processfor treating a chronic obstructive pulmonary disease, which comprisesadministering to a patient in need therefor an effective amount of acompound of claim
 1. 17. A process for treating a chronic obstructivepulmonary disease, which comprises administering to a patient in needtherefor an effective amount of a compound of claim
 4. 18. A process fortreating arthritis, rheumatoid arthritis, spondylitis, osteoarthritis,sepsis, septic shock, gram negative sepsis, toxic shock syndrome,respiratory distress syndrome, asthma, chronic pulmonary disorders, boneresorption diseases, transplant rejection reactions, autoimmunedisorders, lupus erythematosus, multiple sclerosis, glomerulonephritis,uveitis, insulin dependent diabetes mellitus, chronic demyelinization,malaria, infection-related fever, infection-related myalgia, AIDS,cachexia, bronchial asthma, allergic rhinitis, allergic conjunctivitis,atopic dermatitis, eczema, allergic angiitis, eosinophilic fasciitis,eosinophilic pneumonia, pulmonary infiltration with eosinophilia,urticaria, ulcerative colitis, Crohn's disease, psoriasis, keratosis,pulmonary neutrophilic infiltration, chronic obstructive pulmonarydisease, senile dementia, loss of memory, Parkinson's disease,depression, stroke, intermittent claudication, benign prostatehyperplasia, pollakuria, nycturia, bladder atony, kidney stone colics,and analgesic dependency, which comprises administering to a patient apharmacologically effective amount of a compound of claim
 1. 19. Apharmaceutical preparation which comprises a therapeutically effectiveamount of the compound of claim 1, together with one or more of apharmaceutically acceptable carrier, diluent, and auxiliary ingredient.20. A process for preparing the pharmaceutical preparation of claim 12,which comprises preparing a pharmaceutically acceptable dosage form froma compound of claim 1, and from one or more of a pharmaceuticallyacceptable carrier, diluent, and auxiliary ingredient.